Proteolytic activation cascade of the netherton syndrome-defective protein, LEKTI, in the epidermis: Implications for skin homeostasis

Paola Fortugno, Alberto Bresciani, Chantal Paolini, Chiara Pazzagli, May El Hachem, Marina D'Alessio, Giovanna Zambruno

Research output: Contribution to journalArticle

Abstract

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is the defective protein of the ichthyosiform condition Netherton syndrome (NS). Strongly expressed in the most differentiated epidermal layers, LEKTI is a serine protease inhibitor synthesized as three different high-molecular-weight precursors, which are rapidly processed into shorter fragments and secreted extracellularly. LEKTI polypeptides interact with several proteases to regulate skin barrier homeostasis as well as inflammatory and/or immunoallergic responses. Here, by combining antibody mapping, N-terminal sequencing, and site-specific mutagenesis, we defined the amino-acid sequence of most of the LEKTI polypeptides physiologically generated in human epidermis. We also identified three processing intermediates not described so far. Hence, a proteolytic cascade model for LEKTI activation is proposed. We then pinpointed the most effective fragments against the desquamation-related kallikreins (KLKs) and we proved that LEKTI is involved in stratum corneum shedding as some of its polypeptides inhibit the KLK-mediated proteolysis of desmoglein-1. Finally, we quantified the individual LEKTI fragments in the uppermost epidermis, showing that the ratios between LEKTI polypeptides and active KLK5 are compatible with a fine-tuned inhibition. These findings are relevant both to the understanding of skin homeostasis regulation and to the design of novel therapeutic strategies for NS.

Original languageEnglish
Pages (from-to)2223-2232
Number of pages10
JournalJournal of Investigative Dermatology
Volume131
Issue number11
DOIs
Publication statusPublished - Nov 2011

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Proteolytic activation cascade of the netherton syndrome-defective protein, LEKTI, in the epidermis: Implications for skin homeostasis'. Together they form a unique fingerprint.

  • Cite this